Inflammatory arthritis is a prominent clinical manifestation in diverse autoimmune disorders including rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), Sjogren's syndrome and polymyositis.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 0.5 to 1% of the adult population in northern Europe and North America. It is a systemic inflammatory disease characterized by chronic inflammation in the synovial membrane of affected joints, which ultimately leads to loss of daily function due to chronic pain and fatigue. The majority of patients also experience progressive deterioration of cartilage and bone in the affected joints, which may eventually lead to permanent disability. The long-term prognosis of RA is poor, with approximately 50% of patients experiencing significant functional disability within 10 years from the time of diagnosis. Life expectancy is reduced by an average of 3-10 years.
Inflammatory bone diseases, such as RA, are accompanied by bone loss around affected joints due to increased osteoclastic resorption. This process is mediated largely by increased local production of pro-inflammatory cytokines, of which tumor necrosis factor-α (TNF-α) is a major effector.
In RA specifically, an immune response is thought to be initiated/perpetuated by one or several antigens presenting in the synovial compartment, producing an influx of acute inflammatory cells and lymphocytes into the joint. Successive waves of inflammation lead to the formation of an invasive and erosive tissue called pannus. This contains proliferating fibroblast-like synoviocytes and macrophages that produce proinflammatory cytokines such as TNF-α and interleukin-1 (IL-1). Local release of proteolytic enzymes, various inflammatory mediators, and osteoclast activation contribute to much of the tissue damage. There is loss of articular cartilage and the formation of bone erosion. Surrounding tendons and bursa may become affected by the inflammatory process. Ultimately, the integrity of the joint structure is compromised, producing disability.
B cells are thought to contribute to the immunopathogenesis of RA, predominantly by serving as the precursors of autoantibody-producing cells but also as antigen presenting cells (APC) and pro-inflammatory cytokine producing cells. Autoantibodies such as rheumatoid factor (RF) are detected in the serum and synovial fluid of RA patients. Although the sensitivity of RF in diagnosing RA is 30%-70% in early cases and 80%-85% in progressive cases, the specificity of RF is only ˜40%. The presence of serum anti-immunoglobulin binding protein (BiP) antibodies has been reported in RA sera, and anti-BiP antibodies showed similar sensitivity and specificity as RF. BiP concentrations are elevated in the synovial fluid of RA patients and BiP-responsive T cells are also detected in RA patients. Anti-citrullinated protein/peptide antibodies (ACPAs) have been reported to be specific in the diagnosis of RA and the sensitivity and specificity of anti-CCP antibodies in the diagnosis of RA are 60%-80% and 95%-98%, respectively. A number of additional autoantibody specificities have also been associated with RA, including antibodies to Type II collagen and proteoglycans. The generation of large quantities of these antibodies may lead to immune complex formation and the activation of the complement cascade. This in turn amplifies the immune response and may culminate in local cell lysis.
Current standard therapies for RA which are used to modify the disease process and to delay joint destruction are known as disease modifying anti-rheumatic drugs (DMARDs). Examples of DMARDs include methotrexate, leflunomide and sulfasalazine.
Biologic agents designed to target specific components of the immune system that play role in RA are also used as therapeutics. There are various groups of biologic treatments for RA including: TNF-α inhibitors (etanercept, infliximab and adalimumab), B cell targeted therapy (Rituximab), human IL-1 receptor antagonist (anakinra) and selective co-stimulation modulators (abatacept).
Despite the identification of a number of auto-antibodies associated with RA and improved knowledge of the aetiology of the disease, there remains a subset of patients who do not respond adequately to current therapies.
Further understanding of the molecular mechanisms underlying RA is required. Thus there is a need for the provision of relevant autoantibodies associated with RA.